Hypertension is a complex disorder that involves multiple organ systems. Even though the role of immune cells (e.g., macrophages and T lymphocytes) is well accepted in hypertension, the underlying mechanisms are not completely understood. Our major hypothesis is that immune response in hypertension depends on a continuous interaction between immune-activated vascular cells, innate and adaptive immunity. Survival is very important for vascular cells in hypertension. We recently confirmed the pathogenic role for Axl, a receptor tyrosine kinase, on vascular dysfunction in the late phase of salt-sensitive hypertension. Axl-dependent pathways protect hypertensive vasculature from apoptosis. Preliminary data support our working hypothesis that Axl is a key regulator of the immune response in hypertension. We propose three specific aims to test the hypothesis and dissect mechanisms by which Axl regulates the immune response in hypertension. First, we will determine Axl-dependent effects on modulation of immune activation of vascular cells in hypertension. Second, we will identify innate immune cell types that are engaged in Axl-dependent vascular dysfunction in hypertension. Third, we will investigate the regulatory role of Axl in adaptive immunity (CD4 T lymphocytes) that maintains vascular dysfunction in hypertension. Our studies will provide new insights into the pathological mechanisms that regulate vascular dysfunction in hypertension. In particular, we will refine the current concept of the immune response in hypertension and emphasize the importance of retention (via survival) of immune cells in the artery wall at the later phases of hypertension. Finally, Axl-dependent molecular mechanisms can offer a novel therapeutic target for the treatment of hypertension. PUBLIC HEALTH RELEVANCE: This proposal will refine the current concept of vascular dysfunction in hypertension and emphasize the importance of the immune mechanisms in later phases of hypertension. These data will set a strong base for development of original diagnostic tools and/or therapeutic target(s) to treat hypertension.